1. Field of Invention
Cisplatin (cis-dichlorodiammine platinum II) is one of the more effective drugs used in cancer chemotherapy; however, the resulting violent emesis interferes with acceptance of therapy by the patient. This invention relates to an improvement in the method of alleviating emesis caused by cisplatin with metoclopramide, more specifically with extremely high dosages of metoclopramide administered starting prior to and continuing after cisplatin administration.
2. Information Disclosure Statement
Cisplatin is generally acknowledged to be one of the most emetogenic drugs now available for the chemotherapy of malignant diseases in humans. Though it represents a significant advance in the treatment of human cancer, its use nevertheless provokes vomiting which is particularly violent for several hours in almost all of those to whom it is administered. Patients often refuse further treatment because of its severity. Thus, potentially beneficial effects are jeopardized and effects already achieved are negated by the failure of currently available antiemetics or dosage regimen to consistently relieve or, at the very least to even provide expectancy for reduction in severity and frequency of vomiting.
Standard antiemetics have heretofore been of little value in treating side effects of cisplatin in cancer therapy according to Rosenberg, B. in "Cisplatin, Current Studies and New Developments, "Academic Press, Inc., N. Y., N. Y. pp. 9-20 (1980). Metoclopramide has been used in some diagnostic studies of the gastrointestinal tract in the treatment of vomiting of various etiologies and in a variety of functional and organic gastrointestinal disorders. Results of prior studies on attempts to employ metoclopramide against vomiting caused by cisplatin are somewhat contradictory. Kahn T., et al in Cancer Treatment Report 62 (7): 1106-7 July 1968, reports beneficial antiemetic effect in a single oral dose of two 10 mg metoclopramide tablets per patient 3 hours after administration in patients who had already been treated with combination chemotherapy with several other drugs and cisplatin. In an effort to confirm Kahn's work, Arnold, D. J., et al, reporting in Proc AACR & ASCO 21, 334 (1980) conducted a double-blind study in fifteen patients utilizing 20 mg administration of metoclopramide 30 minutes before and 3 hours after cisplatin administration. The test were terminated because of the lack of effectiveness in significantly ameliorating cisplatin emesis. Higi, M., in Deut. Med. Wochenschr. 105 (22) 794-5 (1980), found metoclopramide, triflupromazine and other phenothiazines all ineffective against platinum induced gastrointestinal toxicity. Gylys, J. A. in Res. Commun. in Chem. Path. Pharm. 23 (1): 62-8 (1979) found metoclopramide (1, 3 mg/kg) subcutaneously administered effective in dogs against cisplatin induced emesis.
The present invention is based on the discovery that control of emesis due to cisplatin administration in humans can be consistently overcome by matching extremely high doses of metoclopramide to high doses of cisplatin. Generally, the higher the dose of cisplatin the higher the dose of metoclopramide needed.
The present invention utilizes from about 10 to about 40 times the total dosage used per treatment in humans by Kahn, et al described above.